U.S. patent application number 12/221574 was filed with the patent office on 2009-03-26 for 1-aminocyclohexane derivatives for the treatment of multiple sclerosis, emotional lability and pseudobulbar affect.
This patent application is currently assigned to MERZ PHARMA GMBH & CO. KGAA. Invention is credited to Wojciech Danysz, Jeffrey Jonas, Allison Mann, Christopher Graham Raphael Parsons.
Application Number | 20090081259 12/221574 |
Document ID | / |
Family ID | 36084339 |
Filed Date | 2009-03-26 |
United States Patent
Application |
20090081259 |
Kind Code |
A1 |
Jonas; Jeffrey ; et
al. |
March 26, 2009 |
1-Aminocyclohexane derivatives for the treatment of multiple
sclerosis, emotional lability and pseudobulbar affect
Abstract
The present invention relates to the treatment of individuals
diagnosed with multiple sclerosis, emotional lability or
pseudobulbar affect comprising administering to said individual an
effective amount of a 1-aminocyclohexane derivative, namely
memantine or neramexane.
Inventors: |
Jonas; Jeffrey; (Hoboken,
NJ) ; Mann; Allison; (Fort Lee, NJ) ; Parsons;
Christopher Graham Raphael; (Nidderau, DE) ; Danysz;
Wojciech; (Nidderau, DE) |
Correspondence
Address: |
THE FIRM OF HUESCHEN AND SAGE
SEVENTH FLOOR, KALAMAZOO BUILDING, 107 WEST MICHIGAN AVENUE
KALAMAZOO
MI
49007
US
|
Assignee: |
MERZ PHARMA GMBH & CO.
KGAA
FRANKFURT AM MAIN
DE
|
Family ID: |
36084339 |
Appl. No.: |
12/221574 |
Filed: |
August 5, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11315581 |
Dec 21, 2005 |
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12221574 |
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60638423 |
Dec 22, 2004 |
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Current U.S.
Class: |
424/278.1 ;
514/579 |
Current CPC
Class: |
A61P 25/00 20180101;
A61K 31/13 20130101 |
Class at
Publication: |
424/278.1 ;
514/579 |
International
Class: |
A61K 31/13 20060101
A61K031/13 |
Claims
1. A method of treating multiple sclerosis, emotional lability or
pseudobulbar affect in a subject in need thereof, comprising
administering an effective amount of a 1-aminocyclohexane
derivative and an immunomodulator.
2. The method of claim 1, wherein the 1-aminocyclohexane derivative
and the immunomodulator are administered conjointly.
3. The method of claim 2, wherein the 1-aminocyclohexane derivative
and the immunomodulator are administered in a single
formulation.
4. The method of claim 1, wherein the 1-aminocyclohexane is
represented by the general formula (I): ##STR00004## wherein: R* is
--(A).sub.n--(CR.sup.1R.sup.2).sub.m--NR.sup.3R.sup.4, n,
m=integers from 0 to 2, A is selected from the group consisting of
linear or branched lower alkyl (C.sub.1-C.sub.6), linear or
branched lower alkenyl (C.sub.2-C.sub.6), and linear or branched
lower alkynyl (C.sub.2-C.sub.6), R.sup.1 and R.sup.2 are
independently selected from the group consisting of hydrogen,
linear or branched lower alkyl (C.sub.1-C.sub.6), linear or
branched lower alkenyl (C.sub.2-C.sub.6), linear or branched lower
alkynyl (C.sub.2-C.sub.6) aryl, substituted aryl and arylalkyl, 32
MERZ 54 DIV R.sup.3 and R.sup.4 are independently selected from the
group consisting of hydrogen, linear or branched lower alkyl
(C.sub.1-C.sub.6), linear or branched lower alkenyl
(C.sub.2-C.sub.6), and linear or branched lower alkynyl
(C.sub.2-C.sub.6), or together form alkylene (C.sub.2-C.sub.10) or
alkenylene (C.sub.2-C.sub.10) or together with the N form a
3-7-membered azacycloalkane or azacycloalkene, including
substituted (alkyl (C.sub.1-C.sub.6), alkenyl (C.sub.2-C.sub.6))
3-7-membered azacycloalkane or azacycloalkene; or independently
R.sup.3 or R.sup.4 may join with R.sup.p, R.sup.q, R.sup.r, or
R.sup.s to form an alkylene chain
--CH(R.sup.6)--(CH.sub.2).sub.t--, wherein t=0 or 1 and the left
side of the alkylene chain is attached to U or Y and the right side
of the alkylene chain is attached to N and R.sup.6 is selected from
the group consisting of hydrogen, linear or branched lower alkyl
(C.sub.1-C.sub.6), linear or branched lower alkenyl
(C.sub.2-C.sub.6), linear or branched lower alkynyl
(C.sub.2-C.sub.6), aryl, substituted aryl and arylalkyl; or
independently R.sup.3 or R.sup.4 may join with R.sup.5 to form an
alkylene chain represented by the formula
--CH.sub.2--CH.sub.2--CH.sub.2--(CH.sub.2).sub.t--, or an
alkenylene chain represented by the formulae
--CH.dbd.CH--CH.sub.2--(CH.sub.2).sub.t--,
--CH.dbd.C.dbd.CH--(CH.sub.2).sub.t-- or
--CH.sub.2--CH.dbd.CH--(CH.sub.2).sub.t--, wherein t=0 or 1, and
the left side of the alkylene or alkenylene chain is attached to W
and the right side of the alkylene ring is attached to N; R.sup.5
is independently selected from the group consisting of hydrogen,
linear or branched lower alkyl (C.sub.1-C.sub.6), linear or
branched lower alkenyl (C.sub.2-C.sub.6), and linear or branched
lower alkynyl (C.sub.2-C.sub.6), or R.sup.5 combines with the
carbon to which it is attached and the next adjacent ring carbon to
form a double bond, R.sup.p, R.sup.q, R.sup.r, and R.sup.s, are
independently selected from the group consisting of hydrogen,
linear or branched lower alkyl (C.sub.1-C.sub.6), linear or
branched lower alkenyl (C.sub.2-C.sub.6), linear or branched lower
alkynyl (C.sub.2-C.sub.6), cycloalkyl (C.sub.3-C.sub.6) and aryl,
substituted aryl and arylaklyl or R.sup.p, R.sup.q, R.sup.r, and
R.sup.s independently may form a double bond with U or with Y or to
which it is attached, or R.sup.p, R.sup.q, R.sup.r, and R.sup.s may
combine together to represent a lower alkylene --(CH.sub.2).sub.x--
or a lower alkenylene bridge wherein x is 2-5, inclusive, which
alkylene bridge may, in turn, combine with R.sup.5 to form an
additional lower alkylene --(CH.sub.2).sub.y-- or a lower
alkenylene bridge, wherein y is 1-3, inclusive, the symbols U, W,
and Y represent carbon atoms, the symbols V, X and Z represent
--(CH.sub.2)--, and include optical isomers, diastereomers,
enantiomers, solvates, 33 MERZ 54 DIV hydrates, pharmaceutically
acceptable salts, and mixtures of compounds within formula (I).
5. The method of claim 1, wherein the 1-aminocyclohexane derivative
is selected from neramexane and prodrugs, salts, isomers, analogs
derivatives thereof.
6. The method of claim 1, wherein the immunomodulator is selected
from glatiramer acetate and prodrugs, salts, isomers, analogs
derivatives thereof.
7. A pharmaceutical composition for treatment multiple sclerosis,
emotional lability or pseudobulbar affect, comprising a
1-aminocyclohexane derivative, an immunomodulator and a
pharmaceutically acceptable carrier or excipient, wherein the
1-aminocyclohexane derivative and the immunomodulator are present
at therapeutically effective dosages.
8. The pharmaceutical composition of claim 7, wherein the
1-aminocyclohexane is represented by the general formula (I):
##STR00005## wherein: R* is --(A).sub.n--
(CR.sup.1R.sup.2).sub.m--NR.sup.3R.sup.4, n, m=integers from 0 to
2, A is selected from the group consisting of linear or branched
lower alkyl (C.sub.1-C.sub.6), linear or branched lower alkenyl
(C.sub.2-C.sub.6), and linear or branched lower alkynyl
(C.sub.2-C.sub.6), R.sup.1 and R.sup.2 are independently selected
from the group consisting of hydrogen, linear or branched lower
alkyl (C.sub.1-C.sub.6), linear or branched lower alkenyl
(C.sub.2-C.sub.6), linear or branched lower alkynyl
(C.sub.2-C.sub.6) aryl, substituted aryl and arylalkyl, R.sup.3 and
R.sup.4 are independently selected from the group consisting of
hydrogen, linear or branched lower alkyl (C.sub.1-C.sub.6), linear
or branched lower alkenyl (C.sub.2-C.sub.6), and linear or branched
lower alkynyl (C.sub.2-C.sub.6), or together form alkylene
(C.sub.2-C.sub.10) or alkenylene (C.sub.2-C.sub.10) or together
with the N form a 3-7-membered azacycloalkane or azacycloalkene,
including substituted (alkyl (C.sub.1-C.sub.6), alkenyl
(C.sub.2-C.sub.6)) 3-7-membered azacycloalkane or azacycloalkene;
or independently R.sup.3 or R.sup.4 may join with R.sup.p, R.sup.q,
R.sup.r, or R.sup.s to form an alkylene chain
--CH(R.sup.6)--(CH.sub.2).sub.t--, wherein t=0 or 1 and the left
side of the alkylene chain is attached to U or Y and the right side
of the alkylene chain is attached to N and R.sup.6 is selected from
the group consisting of hydrogen, linear or branched lower alkyl
(C.sub.1-C.sub.6), linear or branched lower alkenyl
(C.sub.2-C.sub.6), linear or branched lower alkynyl
(C.sub.2-C.sub.6), aryl, substituted aryl and arylalkyl; or
independently R.sup.3 or R.sup.4 may join with R.sup.5 to form an
alkylene chain represented by the formula
--CH.sub.2--CH.sub.2--CH.sub.2--(CH.sub.2).sub.t--, or an
alkenylene chain represented by the formulae
--CH.dbd.CH--CH.sub.2--(CH.sub.2).sub.t--,
--CH.dbd.C.dbd.CH--(CH.sub.2).sub.t-- or
--CH.sub.2--CH.dbd.CH--(CH.sub.2).sub.t--, wherein t=0 or 1, and
the left side of the alkylene or alkenylene chain is attached to W
and the right side of the alkylene ring is attached to N; R.sup.5
is independently selected from the group consisting of hydrogen,
linear or branched lower alkyl (C.sub.1-C.sub.6), linear or
branched lower alkenyl (C.sub.2-C.sub.6), and linear or branched
lower alkynyl (C.sub.2-C.sub.6), or R.sup.5 combines with the
carbon to which it is attached and the next adjacent ring carbon to
form a double bond, R.sup.p, R.sup.q, R.sup.r, and R.sup.s, are
independently selected from the group consisting of hydrogen,
linear or branched lower alkyl (C.sub.1-C.sub.6), linear or
branched lower alkenyl (C.sub.2-C.sub.6), linear or branched lower
alkynyl (C.sub.2-C.sub.6), cycloalkyl (C.sub.3-C.sub.6) and aryl,
substituted aryl and arylaklyl or R.sup.p, R.sup.q, R.sup.r, and
R.sup.s independently may form a double bond with U or with Y or to
which it is attached, or R.sup.p, R.sup.q, R.sup.r, and R.sup.s may
combine together to represent a lower alkylene --(CH.sub.2).sub.x--
or a lower alkenylene bridge wherein x is 2-5, inclusive, which
alkylene bridge may, in turn, combine with R.sup.5 to form an 35
MERZ 54 DIV additional lower alkylene --(CH.sub.2).sub.y-- or a
lower alkenylene bridge, wherein y is 1-3, inclusive, the symbols
U, W, and Y represent carbon atoms, the symbols V, X and Z
represent --(CH.sub.2)--, and include optical isomers,
diastereomers, enantiomers, solvates, hydrates, pharmaceutically
acceptable salts, and mixtures of compounds within formula (I).
9. The pharmaceutical composition of claim 7, wherein the
1-aminocyclohexane derivative is selected from neramexane and
prodrugs, salts, isomers, analogs derivatives thereof.
10. The pharmaceutical composition of claim 7, wherein the
immunomodulator is selected from glatiramer acetate and prodrugs,
salts, isomers, analogs derivatives thereof.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to the treatment of
individuals diagnosed with multiple sclerosis, emotional lability
or pseudobulbar affect comprising administering to said individual
an effective amount of a 1-aminocyclohexane derivative.
BACKGROUND OF THE INVENTION
[0002] This invention relates to methods of treating patients
suffering from multiple sclerosis (MS) or emotional problems that
occur in relation to neurodegenerative diseases or to brain damage
such as caused by stroke or head injury.
[0003] Multiple sclerosis is a disease of the central nervous
system and results in the progressive loss of certain body
functions and physical abilities. MS is a progressive and usually
fluctuating disease with exacerbations (patients feeling worse) and
remissions (patients feeling better) over many decades. Eventually,
in most patients, remissions do not reach baseline levels and
permanent disability and sometimes death occurs. The cause of MS is
unknown.
[0004] Emotional lability (EL) is a disease of the central nervous
system whereby the patient experiences rapid and sizeable mood
changes that can be easily provoked and can rapidly disappear. It
is thought to result from an underlying defect in the voluntary
control (cognitive) of emotional reactions. Pseudobulbar affect
(PBA) is a more severe form of emotional lability in which there
are uncontrollable episodes of laughing and/or crying that are
unpredictable and seem to have little or no relationship to actual
events or the individual's actual feelings.
[0005] Various therapeutic approaches have been used in the
treatment of MS. Immunomodulators, including glatiramer acetate,
have been demonstrated to be effective in improving symptoms
associated with MS.
[0006] NMDA receptor antagonists potentially have a wide range of
therapeutic applications in numerous CNS disorders such as acute
neurodegeneration associated with stroke and trauma, chronic
neurodegeneration associated with Parkinson's diseases such as
Alzheimer's disease, Huntington's disease, amyotrophic lateral
sclerosis (ALS), epilepsy, drug dependence, depression, anxiety,
and chronic pain (see: Parsons et al., Drug News Perspect., 1998,
11:523-533; Parsons et al., 1999, supra; Jentsch and Roth,
Neuropsychopharmacology, 1999, 20: 201-205; Doble, Therapie, 1995,
50: 319-337). Many NMDA receptor antagonists identified to date
produce highly undesirable side effects at doses within their
putative therapeutic range. Thus, clinical trials failed to support
good therapeutic utility due to numerous side effects for such NMDA
receptor antagonists as Dizocilpine ((+)MK-801;
(+)-5-methyl-10,11-dihydro-5H-dibenzocyclohepten-5,10-imine
maleate), Cerestat (CNS-1102), Licostinel (ACEA 1021), Selfotel
(CGS-19755), and D-CPP-ene (Leppik, Epilepsia, 1998, 39 (Suppl
5):2-6; Sveinbjornsdottir et al., Epilepsia, 1993, 34:493-521;
SCRIP 2229/30, 1997, p. 21).
[0007] Memantine (1-amino-3,5-dimethyl adamantane) and neramexane
(1-amino-1,3,3,5,5-pentamethylcyclohexane), two NMDA receptor
antagonists and analogs of 1-aminocyclo-hexane, prevent the
pathological activation of NMDA receptors but allow their
physiological activity. Both memantine and neramexane, as well as
some other 1-aminoalkyl-cyclohexanes, are systemically-active
noncompetitive NMDA receptor antagonists having moderate affinity
for the receptor. They exhibit strong voltage dependent
characteristics and fast blocking/unblocking kinetics (Parsons et
al., 1999, supra; Winblad et al., Int. J. Geriat. Psychiatry, 1999,
14:135-146; Rogawski, Amino Acids, 2000, 19: 133-49; Danysz et al.,
Curr. Pharm. Des., 2002, 8:835-43; Jirgensons et. al., Eur. J. Med.
Chem., 2000, 35: 555-565). These compounds dissociate from the NMDA
receptor channels much more rapidly than the high affinity NMDA
receptor antagonists such as (+)MK-801 and attenuate disruption of
neuronal plasticity produced by tonic overstimulation of NMDA
receptors probably by causing an increase of the signal-to-noise
ratio. Due to their relatively low affinity for the receptor,
strong voltage dependency and fast receptor unblocking kinetics,
these compounds are essentially devoid of the side effects of other
NMDA receptor antagonists at doses within the therapeutic
range.
[0008] Memantine, neramexane as well as other
1-aminoalkylcyclohexanes have been suggested to be useful in
alleviation of various progressive neurodegenerative disorders such
as dementia in AD, Parkinson's disease, and spasticity (see U.S.
Pat. Nos. 5,061,703; 5,614,560; and 6,034,134; Parsons et al.,
1999, supra; Mobius, ADAD, 1999,13:S172-178; Danysz et al.,
Neurotox. Res., 2000, 2:85-97; Winblad and Poritis, Int. J.
Geriatr. Psychiatry, 1999, 14:135-146; Gortelmeyer et al., 1992,
supra; Danysz et al., Curr. Pharm. Des., 2002, 8:835-843;
Jirgensons et. al., Eur. J. Med. Chem., 2000, 35: 555-565). These
diseases result from disturbances of glutamatergic transmission,
i.e., the excessive influx of calcium through NMDA receptor
channels, leading to the destruction of brain cells in specific
brain areas (Choi, J. Neurobiol., 23: 1261-1276, 1992; Rothman and
Olney, Trends Neurosci., 10: 299, 1987; Kemp et al., Trends
Pharmacol. Sci., 8: 414, 1987). Treatment of adult rats with
memantine has been shown to enhance the formation of hippocampal
long-term potentiation, increase the durability of synaptic
plasticity, improve spatial memory abilities, and reverse the
memory impairment produced by NMDA receptor agonists (Barnes et
al., Eur. J. Neurosci., 1996; 8:565-571; Zajaczkowski et al.,
Neuropharm, 1997, 36:961-971). 1-Aminocyclohexane derivatives, and
specifically memantine, have also been suggested to be useful in
the treatment of AIDS dementia (U.S. Pat. No. 5,506,231),
neuropathic pain (U.S. Pat. No. 5,334,618), cerebral ischemia (U.S.
Pat. No. 5,061,703), epilepsy, glaucoma, hepatic encephalopathy,
multiple sclerosis, stroke, and tardive dyskinesia (Parsons et al.,
1999, supra). Furthermore, relatively high doses of memantine and
neramexane were shown to selectively block thermal hyperalgesia and
mechanical allodynia in some models of chronic and neuropathic pain
without obvious effects on motor reflexes. 1-Aminocyclohexane
derivatives were also demonstrated to possess immunomodulatory,
antimalarial, anti-Borna virus, and anti-Hepatitis C activities
(see, e.g., U.S. Pat. No. 6,034,134 and references cited
therein).
[0009] U.S. Pat. No. 5,206,248 ('248) describes the treatment of
emotional lability by administration of a non-addictive analog of
morphine, dextromethorphan or dextrorphan, as a mono-therapy or in
combination with quinine. One known mechanism of action for
Dextromethorphan includes as a NMDA receptor antagonist. PCT Patent
Application 2004/006930 ('930) describes the treatment of
neurological disorders including multiple sclerosis, emotional
lability and pseudobulbar affect using a combination therapy of a
non-addictive analog of morphine, dextromethorphan or dextrorphan,
in combination with quinine.
[0010] Memantine has been investigated to treat neurological
deficits in Lewis rat experimental autoimmune encephalomyelitis
(EAE). (Bolton, J. Pharmacol Exp Ther. 2002, July; 302(1): 50-57;
Wallstrom, J. Neurol. Sci. 1996, 137, 89-96). Although EAE is the
typical animal model of MS, it is not multiple sclerosis, nor is
EAE a single disease in a single species. EAEs different forms only
resemble the various forms, symptoms and stages of MS. Those forms
and symptoms vary greatly depending on the species of rodent used.
Additionally, the Lewis rat experiments only studied memantine only
to a limited extent. The Bolton study only looked at motor symptoms
and histology of the cerebellum, spinal cord, and medulla. Whereas
the Wallstrom study merely suggested the therapeutic effect of
memantine in the EAE model was not due to dampened CNS inflammation
secondary to immune cell activation. The effect of memantine on
frontal cortex or supranuclear structures circuitry was not
assessed. In addition, these EAE experiments are not suitable for
evaluating pseudobulbar affect which occurs in the later stages of
MS. The animals were sacrificed after only 2 days. Moreover, an EAE
model is generally not applicable for testing emotional lability or
pseudobulbar affect symptoms which most notably include
uncontrollable emotional expressions.
[0011] Memantine has been shown effective for the treatment of
acquired pendular nystagmus, a physical symptom of the underlying
condition of multiple sclerosis. (Curr. Treat Options Neurol. 1999
March;1(1):68-73) Yet, this invention demonstrates for the first
time that the clinical administration of memantine, a
1-aminocyclohexane derivative, is effective for the treatment of
cognitive dysfunction associated with multiple sclerosis. It will
be shown that MS patients with cognitive impairment treated with
memantine demonstrate unexpected improvement in performance on a
neuropsychological test battery as compared to placebo treated
patients.
SUMMARY OF THE INVENTION
[0012] The present invention relates to the treatment of
individuals diagnosed with multiple sclerosis, emotional lability
or pseudobulbar affect comprising administering to said individual
an 1-aminocyclohexane derivative.
[0013] In a specific embodiment of the instant invention, the
1-aminocyclohexane is selected from memantine, neramexane, and
derivatives thereof, including pharmaceutically acceptable salts
and analogs of these active agents.
[0014] A further aspect of the invention relates to the treatment
of individuals diagnosed with multiple sclerosis, emotional
lability or pseudobulbar affect comprising administering to said
individual an 1-aminocyclohexane derivative and an additional
pharmaceutical agent which has been shown to be effective in
treating MS, EL and PBA.
[0015] A further aspect of the invention relates to the treatment
of individuals diagnosed with multiple sclerosis, emotional
lability or pseudobulbar affect comprising administering to said
individual an 1-aminocyclohexane derivative and an
immunomodulator.
[0016] In a specific embodiment of the instant invention the
1-aminocyclohexane is selected from memantine, neramexane, and
derivatives thereof, including pharmaceutically acceptable salts
and analogs of these active agents, and the immunomodulator is
selected from glatiramer acetate and derivatives thereof, including
pharmaceutically acceptable salts and analogs of these active
agents.
[0017] A further aspect of the invention includes a pharmaceutical
composition comprising a therapeutically effective amount of a
1-aminocyclohexane, alone or in combination with other therapies
for MS, EL and PBA and, optionally, at least one pharmaceutically
acceptable carrier or excipient.
[0018] A further aspect of the invention includes a pharmaceutical
composition comprising a therapeutically effective amount of a
1-aminocyclohexane, an immunomodulator and at least one
pharmaceutically acceptable carrier or excipient.
[0019] A further aspect of the invention includes a pharmaceutical
composition comprising a therapeutically effective amount of a
1-aminocyclohexane derivative in an immediate or modified release
formulation.
[0020] A further aspect of the invention includes a pharmaceutical
composition comprising a therapeutically effective amount of a
1-aminocyclohexane derivative and an immunomodulator in an
immediate or modified release formulation.
BRIEF DESCRIPTION OF THE DRAWINGS
[0021] FIGS. 1A and 1B depict the protocol for EAE inducement and
symptomatic progression in animal models.
[0022] FIG. 2 is a plot of the resistance to flexion (N) over time
post-injection (minutes). The data points reflect the neramexane
dose at 3.1 mg/kg.
[0023] FIG. 3 is a plot of the resistance to flexion (N) over time
post-injection (minutes). The data points reflect the neramexane
dose at 6.2 mg/kg.
[0024] FIG. 4 is a plot of the resistance to flexion (N) over time
post-injection (minutes). The data points reflect the neramexane
dose at 12.3 mg/kg.
DETAILED DESCRIPTION OF THE INVENTION
[0025] The term "treat" is used herein to mean to relieve or
alleviate at least one symptom of a disease in a subject. Within
the meaning of the present invention, the term "treat" also denotes
to arrest, delay the onset (i.e., the period prior to clinical
manifestation of a disease) and/or reduce the risk of developing or
worsening a disease.
[0026] The term "analog" or "derivative" is used herein in the
conventional pharmaceutical sense, to refer to a molecule that
structurally resembles a reference molecule (such as
1-aminocyclohexane), but has been modified in a targeted and
controlled manner to replace one or more specific substituents of
the referent molecule with an alternate substituent, thereby
generating a molecule which is structurally similar to the
reference molecule. Synthesis and screening of analogs (e.g., using
structural and/or biochemical analysis), to identify slightly
modified versions of a known compound which may have improved or
biased traits (such as higher potency and/or selectivity at a
specific targeted receptor type, greater ability to penetrate
mammalian blood-brain barriers, fewer side effects, etc.) is a drug
design approach that is well known in pharmaceutical chemistry.
[0027] The term "1-aminocyclohexane derivative" is used herein to
describe a compound which is derived from 1-aminocyclohexane (or an
available derivative thereof, such as neramexane or memantine) in
the process used to create a functionally similar but slightly
structurally different drug.
[0028] The 1-aminocyclohexane derivatives of the present invention
can be represented by the general formula (I):
##STR00001##
wherein: R* is
--(A).sub.n--(CR.sup.1R.sup.2).sub.m--NR.sup.3R.sup.4, n,
m=integers from 0 to 2, A is selected from the group consisting of
linear or branched lower alkyl (C.sub.1-C.sub.6), linear or
branched lower alkenyl (C.sub.2-C.sub.6), and linear or branched
lower alkynyl (C.sub.2-C.sub.6), R.sup.1 and R.sup.2 are
independently selected from the group consisting of hydrogen,
linear or branched lower alkyl (C.sub.1-C.sub.6), linear or
branched lower alkenyl (C.sub.2-C.sub.6), linear or branched lower
alkynyl (C.sub.2-C.sub.6) aryl, substituted aryl and arylalkyl,
R.sup.3 and R.sup.4 are independently selected from the group
consisting of hydrogen, linear or branched lower alkyl
(C.sub.1-C.sub.6), linear or branched lower alkenyl
(C.sub.2-C.sub.6), and linear or branched lower alkynyl
(C.sub.2-C.sub.6), or together form alkylene (C.sub.2-C.sub.10) or
alkenylene (C.sub.2-C.sub.10) or together with the N form a
3-7-membered azacycloalkane or azacycloalkene, including
substituted (alkyl (C.sub.1-C.sub.6), alkenyl (C.sub.2-C.sub.6))
3-7-membered azacycloalkane or azacycloalkene; or independently
R.sup.3 or R.sup.4 may join with R.sup.p, R.sup.q, R.sup.r, or
R.sup.s to form an alkylene chain
--CH(R.sup.6)--(CH.sub.2).sub.t--, wherein t=0 or 1 and the left
side of the alkylene chain is attached to U or Y and the right side
of the alkylene chain is attached to N and R.sup.6 is selected from
the group consisting of hydrogen, linear or branched lower alkyl
(C.sub.1-C.sub.6), linear or branched lower alkenyl
(C.sub.2-C.sub.6), linear or branched lower alkynyl
(C.sub.2-C.sub.6), aryl, substituted aryl and arylalkyl; or
independently R.sup.3 or R.sup.4 may join with R.sup.5 to form an
alkylene chain represented by the formula
--CH.sub.2--CH.sub.2--CH.sub.2--(CH.sub.2).sub.t--, or an
alkenylene chain represented by the formulae
--CH.dbd.CH--CH.sub.2--(CH.sub.2).sub.t--,
--CH.dbd.C.dbd.CH--(CH.sub.2).sub.t-- or
--CH.sub.2--CH.dbd.CH--(CH.sub.2).sub.t--, wherein t=0 or 1, and
the left side of the alkylene or alkenylene chain is attached to W
and the right side of the alkylene ring is attached to N; R.sup.5
is independently selected from the group consisting of hydrogen,
linear or branched lower alkyl (C.sub.1-C.sub.6), linear or
branched lower alkenyl (C.sub.2-C.sub.6), and linear or branched
lower alkynyl (C.sub.2-C.sub.6), or R.sup.5 combines with the
carbon to which it is attached and the next adjacent ring carbon to
form a double bond, R.sup.p, R.sup.q, R.sup.r, and R.sup.s, are
independently selected from the group consisting of hydrogen,
linear or branched lower alkyl (C.sub.1-C.sub.6), linear or
branched lower alkenyl (C.sub.2-C.sub.6), linear or branched lower
alkynyl (C.sub.2-C.sub.6), cycloalkyl (C.sub.3-C.sub.6) and aryl,
substituted aryl and arylaklyl or R.sup.p, R.sup.q, R.sup.r, and
R.sup.s independently may form a double bond with U or with Y or to
which it is attached, or R.sup.p, R.sup.q, R.sup.r, and R.sup.s may
combine together to represent a lower alkylene (CH.sub.2).sub.x--
or a lower alkenylene bridge wherein x is 2-5, inclusive, which
alkylene bridge may, in turn, combine with R.sup.5 to form an
additional lower alkylene --(CH.sub.2).sub.y-- or a lower
alkenylene bridge, wherein y is 1-3, inclusive, the symbols U, W,
and Y represent carbon atoms, the symbols V, X and Z represent
--(CH.sub.2)--, and include optical isomers, diastereomers,
enantiomers, solvates, hydrates, pharmaceutically acceptable salts,
and mixtures of compounds within formula (I). The ring defined by
U-V-W-X-Y-Z is preferably selected from the group consisting of
cyclohexane, cyclohex-2-ene, cyclohex-3-ene, cyclohex-1,4-diene,
cyclohex-1,5-diene, cyclohex-2,4-diene, and cyclohex-2,5-diene,
Non-limiting examples of 1-aminocyclohexane derivatives used
according to the invention include the 1-aminoalkylcyclohexane
derivatives selected from the group consisting of: [0029]
1-amino-1,3,5-trimethylcyclohexane, [0030]
1-amino-1(trans),3(trans),5-trimethylcyclohexane, [0031]
1-amino-1(cis),3(cis),5-trimethylcyclohexane, [0032]
1-amino-1,3,3,5-tetramethylcyclohexane, [0033]
1-amino-1,3,3,5,5-pentamethylcyclohexane (neramexane), [0034]
1-amino-1,3,5,5-tetramethyl-3-ethylcyclohexane, [0035]
1-amino-1,5,5-trimethyl-3,3-diethylcyclohexane, [0036]
1-amino-1,5,5-trimethyl-cis-3-ethylcyclohexane, [0037]
1-amino-(1S,5S)cis-3-ethyl-1,5,5-trimethylcyclohexane, [0038]
1-amino-1,5,5-trimethyl-trans-3-ethylcyclohexane, [0039]
1-amino-(1R,5S)trans-3-ethyl-1,5,5-trimethylcyclohexane, [0040]
1-amino-1-ethyl-3,3,5,5-tetramethylcyclohexane, [0041]
1-amino-1-propyl-3,3,5,5-tetramethylcyclohexane, [0042]
N-methyl-1-amino-1,3,3,5,5-pentamethylcyclohexane, [0043]
N-ethyl-1-amino-1,3,3,5,5-pentamethyl-cyclohexane, [0044]
N-(1,3,3,5,5-pentamethylcyclohexyl) pyrrolidine, [0045]
3,3,5,5-tetramethylcyclohexylmethylamine, [0046]
1-amino-1-propyl-3,3,5,5-tetramethylcyclohexane, [0047] 1
amino-1,3,3,5(trans)-tetramethylcyclohexane (axial amino group),
[0048] 3-propyl-1,3,5,5-tetramethylcyclohexylamine semihydrate,
[0049] 1-amino-1,3,5,5-tetramethyl-3-ethylcyclohexane, [0050]
1-amino-1,3,5-trimethylcyclohexane, [0051]
1-amino-1,3-dimethyl-3-propylcyclohexane, [0052]
1-amino-1,3(trans),5(trans)-trimethyl-3(cis)-propylcyclohexane,
[0053] 1-amino-1,3-dimethyl-3-ethylcyclohexane, [0054]
1-amino-1,3,3-trimethylcyclohexane, [0055]
cis-3-ethyl-1(trans)-3(trans)-5-trimethylcyclohexamine, [0056]
1-amino-1,3(trans)-dimethylcyclohexane, [0057]
1,3,3-trimethyl-5,5-dipropylcyclohexylamine, [0058]
1-amino-1-methyl-3(trans)-propylcyclohexane, [0059]
1-methyl-3(cis)-propylcyclohexylamine, [0060]
1-amino-1-methyl-3(trans)-ethylcyclohexane, [0061]
1-amino-1,3,3-trimethyl-5(cis)-ethylcyclohexane, [0062]
1-amino-1,3,3-trimethyl-5(trans)-ethylcyclohexane, [0063]
cis-3-propyl-1,5,5-trimethylcyclohexylamine, [0064]
trans-3-propyl-1,5,5-trimethylcyclohexylamine, [0065]
N-ethyl-1,3,3,5,5-pentamethylcyclohexylamine, [0066]
N-methyl-1-amino-1,3,3,5.5-pentamethylcyclohexane, [0067]
1-amino-1-methylcyclohexane, [0068]
N,N-dimethyl-1-amino-1,3,3,5,5-pentamethylcyclohexane, [0069]
2-(3,3,5,5-tetramethylcyclohexyl)ethylamine, [0070]
2-methyl-1-(3,3,5,5-tetramethylcyclohexyl)propyl-2-amine, [0071]
2-(1,3,3,5,5-pentamethylcyclohexyl)-ethylamine semihydrate, [0072]
N-(1,3,3,5,5-pentamethylcyclohexyl)-pyrrolidine, [0073]
1-amino-1,3(trans),5(trans)-trimethylcyclohexane, [0074]
1-amino-1,3(cis),5(cis)-trimethylcyclohexane, [0075]
1-amino-(1R,5S)trans-5-ethyl-1,3,3-trimethylcyclohexane, [0076]
1-amino-(1S,5S)cis-5-ethyl-1,3,3-trimethylcyclohexane, [0077]
1-amino-1,5,5-trimethyl-3(cis)-isopropyl-cyclohexane, [0078]
1-amino-1,5,5-trimethyl-3(trans)-isopropyl-cyclohexane, [0079]
1-amino-1-methyl-3(cis)-ethyl-cyclohexane, [0080]
1-amino-1-methyl-3(cis)-methyl-cyclohexane, [0081]
1-amino-5,5-diethyl-1,3,3-trimethyl-cyclohexane, [0082]
1-amino-1,3,3,5,5-pentamethylcyclohexane, [0083]
1-amino-1,5,5-trimethyl-3,3-diethylcyclohexane, [0084]
1-amino-1-ethyl-3,3,5,5-tetramethylcyclohexane, [0085]
N-ethyl-1-amino-1,3,3,5,5-pentamethylcyclohexane, [0086]
N-(1,3,5-trimethylcyclohexyl)pyrrolidine or piperidine, [0087]
N-[1,3(trans),5(trans)-trimethylcyclohexyl]pyrrolidine or
piperidine, [0088]
N-[1,3(cis),5(cis)-trimethylcyclohexyl]pyrrolidine or piperidine,
[0089] N-(1,3,3,5-tetramethylcyclohexyl)pyrrolidine or piperidine,
[0090] N-(1,3,3,5,5-pentamethylcyclohexyl)pyrrolidine or
piperidine, [0091]
N-(1,3,5,5-tetramethyl-3-ethylcyclohexyl)pyrrolidine or piperidine,
[0092] N-(1,5,5-trimethyl-3,3-diethylcyclohexyl)pyrrolidine or
piperidine, [0093]
N-(1,3,3-trimethyl-cis-5-ethylcyclohexyl)pyrrolidine or piperidine,
[0094] N-[(1S,5S)cis-5-ethyl-1,3,3-trimethylcyclohexyl]pyrrolidine
or piperidine, [0095]
N-(1,3,3-trimethyl-trans-5-ethylcyclohexyl)pyrrolidine or
piperidine, [0096]
N-[(1R,5S)trans-5-ethyl,3,3-trimethylcyclohexyl]pyrrolidine or
piperidine, [0097]
N-(1-ethyl-3,3,5,5-tetramethylyclohexyl)pyrrolidine or piperidine,
[0098] N-(1-propyl-3,3,5,5-tetramethylcyclohexyl)pyrrolidine or
piperidine, [0099] N-(1,3,3,5,5-pentamethylcyclohexyl)pyrrolidine,
their optical isomers, diastereomers, enantiomers, solvates,
hydrates, their pharmaceutically acceptable salts, and mixtures
thereof.
[0100] Neramexane (1-amino-1,3,3,5,5-pentamethylcyclohexane) is
disclosed in U.S. Pat. No. 6,034,134 which is incorporated here by
reference.
[0101] Certain 1-aminocyclohexane derivatives of general formula
(I) including the case where three axial alkyl substituent, e.g.,
R.sup.p, R.sup.r and R.sup.5 all together form a bridgehead to
yield compounds (so called 1-aminoadamantanes) illustrated by the
formulae IIb-IId below:
##STR00002##
[0102] Certain 1-aminocyclohexane derivatives of formula (I)
wherein n+m=0, U, V, W, X, Y and Z form a cyclohexane ring, and one
or both of R.sup.3 and R.sup.4 are independently joined to said
cyclohexane ring via alkylene bridges formed through R.sup.p,
R.sup.q, R.sup.r, R.sup.s or R.sup.5 are represented by the
following formulae IIIa-IIIc:
##STR00003##
where R.sup.q, R.sup.r, R.sup.s, R.sup.r and R.sup.5 are as defined
above for formula (I), R.sup.6 is hydrogen, linear or branched
lower alkyl (C.sub.1-C.sub.6), linear or branched lower alkenyl
(C.sub.2-C.sub.6), linear or branched lower alkynyl
(C.sub.2-C.sub.6), aryl, substituted aryl or arylalkyl Y is
saturated or may combine with R.sup.6 to form a carbon-hydrogen
bond with the ring carbon to which it is attached, I=0 or 1 and
k=0, 1 or 2 and represents a single or double bond.
[0103] Non-limiting examples of 1-aminocyclohexane derivatives used
according to the invention include 1-amino adamantane and its
derivatives selected from the group consisting of: [0104]
1-amino-3-phenyl adamantane, [0105] 1-amino-methyl adamantane,
[0106] 1-amino-3,5-dimethyl adamantane (memantine), [0107]
1-amino-3-ethyl adamantane, [0108] 1-amino-3-isopropyl adamantane,
[0109] 1-amino-3-n-butyl adamantane, [0110] 1-amino-3,5-diethyl
adamantane, [0111] 1-amino-3,5-diisopropyl adamantane, [0112]
1-amino-3,5-di-n-butyl adamantane, [0113] 1-amino-3-methyl-5-ethyl
adamantane, [0114] 1-N-methylamino-3,5-dimethyl adamantane, [0115]
1-N-ethylamino-3,5-dimethyl adamantane, [0116]
1-N-isopropyl-amino-3,5-dimethyl adamantane, [0117]
1-N,N-dimethyl-amino-3,5-dimethyl adamantane, [0118]
1-N-methyl-N-isopropyl-amino-3-methyl-5-ethyl adamantane, [0119]
1-amino-3-butyl-5-phenyl adamantane, [0120] 1-amino-3-pentyl
adamantane, [0121] 1-amino-3,5-dipentyl adamantane, [0122]
1-amino-3-pentyl-5-hexyl adamantane, [0123]
1-amino-3-pentyl-5-cyclohexyl adamantane, [0124]
1-amino-3-pentyl-5-phenyl adamantane, [0125] 1-amino-3-hexyl
adamantane, [0126] 1-amino-3,5-dihexyl adamantane, [0127]
1-amino-3-hexyl-5-cyclohexyl adamantane, [0128]
1-amino-3-hexyl-5-phenyl adamantane, [0129] 1-amino-3-cyclohexyl
adamantane, [0130] 1-amino-3,5-dicyclohexyl adamantane, [0131]
1-amino-3-cyclohexyl-5-phenyl adamantane, [0132]
1-amino-3,5-diphenyl adamantane, [0133] 1-amino-3,5,7-trimethyl
adamantane, [0134] 1-amino-3,5-dimethyl-7-ethyl adamantane, [0135]
1-amino-3,5-diethyl-7-methyl adamantane, [0136] 1-N-pyrrolidino and
1-N-piperidine derivatives, [0137] 1-amino-3-methyl-5-propyl
adamantane, [0138] 1-amino-3-methyl-5-butyl adamantane, [0139]
1-amino-3-methyl-5-pentyl adamantane, [0140]
1-amino-3-methyl-5-hexyl adamantane, [0141]
1-amino-3-methyl-5-cyclohexyl adamantane, [0142]
1-amino-3-methyl-5-phenyl adamantane, [0143]
1-amino-3-ethyl-5-propyl adamantane, [0144] 1-amino-3-ethyl-5-butyl
adamantane, [0145] 1-amino-3-ethyl-5-pentyl adamantane, [0146]
1-amino-3-ethyl-5-hexyl adamantane, [0147]
1-amino-3-ethyl-5-cyclohexyl adamantane, [0148]
1-amino-3-ethyl-5-phenyl adamantane, [0149]
1-amino-3-propyl-5-butyl adamantane, [0150]
1-amino-3-propyl-5-pentyl adamantane, [0151]
1-amino-3-propyl-5-hexyl adamantane, [0152]
1-amino-3-propyl-5-cyclohexyl adamantane, [0153]
1-amino-3-propyl-5-phenyl adamantane, [0154]
1-amino-3-butyl-5-pentyl adamantane, [0155] 1-amino-3-butyl-5-hexyl
adamantane, [0156] 1-amino-3-butyl-5-cyclohexyl adamantane, their
optical isomers, diastereomers, enantiomers, solvates, hydrates,
N-methyl, N,N-dimethyl, N-ethyl, N-propyl derivatives, their
pharmaceutically acceptable salts, and mixtures thereof.
[0157] Memantine (1-amino-3,5-dimethyl adamantane), for example, is
the subject matter of U.S. Pat. Nos.: 4,122,193, 4,273,774,
5,061,703, and 5,614,560.
[0158] The 1-amino adamantane derivatives of formulae IIb and IId,
including memantine, are generally prepared by alkylation of
halogenated adamantanes, preferably bromo- or chloroadamantanes.
The di- or tri-substituted adamantanes are obtained by additional
halogenation and alkylation procedures. The amino group is
introduced either by oxidation with chromiumtrioxide and
bromination with HBr or bromination with bromine and reaction with
formamide followed by hydrolysis. The amino function can be
alkylated according to generally-accepted methods. Methylation can,
for example, be effected by reaction with chloromethyl formate and
subsequent reduction. The ethyl group can be introduced by
reduction of the respective acetamide. For more details on
synthesis see, e.g., U.S. Pat. Nos. 5,061,703 and 6,034,134.
Additional synthetic techniques for the foregoing compounds can be
found in U.S. Published Applications No. 20030166634 and
20040034055, all incorporated by reference.
[0159] Various salts and isomers (including stereoisomers and
enantiomers) of the drugs listed herein can be used. The term
"salts" can include salts of free acids or free bases. Examples of
acids which may be employed to form pharmaceutically acceptable
acid addition salts include inorganic acids such as hydrochloric,
sulfuric, or phosphoric acid, and organic acids such as acetic,
maleic, succinic, or citric acid, etc. All of these salts (or other
similar salts) may be prepared by conventional means. The nature of
the salt or isomer is not critical, provided that it is non-toxic
and does not substantially interfere with the desired
pharmacological activity.
[0160] The term "therapeutically effective" applied to dose or
amount refers to that quantity of a compound or pharmaceutical
composition that is sufficient to result in a desired activity upon
administration to a mammal in need thereof. As used herein with
respect to the pharmaceutical compositions comprising an
1-aminocyclohexane derivative, the term "therapeutically effective
amount/dose" is used interchangeably with the term "neurologically
effective amount/dose" and refers to the amount/dose of a compound
or pharmaceutical composition that is sufficient to produce an
effective neurological response upon administration to a
mammal.
[0161] The phrase "pharmaceutically acceptable", as used in
connection with compositions of the invention, refers to molecular
entities and other ingredients of such compositions that are
physiologically tolerable and do not typically produce untoward
reactions when administered to a mammal (e.g., human). Preferably,
as used herein, the term "pharmaceutically acceptable" means
approved by a regulatory agency of the Federal or a state
government or listed in the U.S. Pharmacopeia or other generally
recognized pharmacopeia for use in mammals, and more particularly
in humans.
[0162] The term "carrier" applied to pharmaceutical compositions of
the invention refers to a diluent, excipient, or vehicle with which
an active compound (e.g., an 1-aminocyclohexane derivative) is
administered. Such pharmaceutical carriers can be sterile liquids,
such as water, saline solutions, aqueous dextrose solutions,
aqueous glycerol solutions, and oils, including those of petroleum,
animal, vegetable or synthetic origin, such as peanut oil, soybean
oil, mineral oil, sesame oil and the like. Suitable pharmaceutical
carriers are described in "Remington's Pharmaceutical Sciences" by
E. W. Martin, 18.sup.th Edition.
[0163] The term "about" or "approximately" usually means within
20%, more preferably within 10%, and most preferably still within
5% of a given value or range. Alternatively, especially in
biological systems, the term "about" means within about a log
(i.e., an order of magnitude) preferably within a factor of two of
a given value.
[0164] In conjunction with the methods of the present invention,
also provided are pharmaceutical compositions comprising a
therapeutically effective amount of a 1-aminocyclohexane
derivative. The compositions of the invention further can comprise
a carrier or excipient (all pharmaceutically acceptable). The
compositions can be formulated for once-a-day administration or
twice-a-day administration. The preferred 1-aminocyclohexane
derivatives are memantine and neramexane.
[0165] Memantine (NAMENDA.TM.) is commercially available as the
hydrochloride salt in 5 or 10 mg film-coated tablets. However,
according to the present invention, the dosage form of memantine
may be a solid, semisolid or liquid formulation according to the
following.
[0166] The 1-aminocyclohexane derivative may be administered
orally, topically, parenterally, or mucosally (e.g., buccally, by
inhalation, or rectally) in dosage unit formulations containing
conventional non-toxic pharmaceutically acceptable carriers. In one
embodiment for the administration to pediatric subjects, memantine
is formulated as a flavored liquid, e.g., peppermint flavor. The
1-aminocyclohexane derivative may be administered orally in the
form of a capsule, a tablet, or the like, or as a semi-solid or
liquid formulation (see Remington's Pharmaceutical Sciences, Mack 5
Publishing Co., Easton, Pa.).
[0167] For oral administration in the form of a tablet or capsule,
the 1-aminocyclohexane derivative can be combined with a non-toxic,
pharmaceutically acceptable excipients such as binding agents
(e.g., pregelatinized maize starch, polyvinylpyrrolidone or
hydroxypropyl methylcellulose); fillers (e.g., lactose, sucrose,
glucose, mannitol, sorbitol and other reducing and non-reducing
sugars, microcrystalline cellulose, calcium sulfate, or calcium
hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, or
silica, steric acid, sodium stearyl fumarate, glyceryl behenate,
calcium stearate, and the like); disintegrants (e.g., potato starch
or sodium starch glycolate); or wetting agents (e.g., sodium lauryl
sulphate), coloring and flavoring agents, gelatin, sweeteners,
natural and synthetic gums (such as acacia, tragacanth or
alginates), buffer salts, carboxymethylcellulose,
polyethyleneglycol, waxes, and the like.
[0168] The tablets can be coated with a concentrated sugar solution
which may contain e.g., gum arabic, gelatine, talcum, titanium
dioxide, and the like. Alternatively, the tablets can be coated
with a polymer that dissolves in a readily volatile organic solvent
or mixture of organic solvents. In specific embodiments, memantine
is formulated in to immediate-release (IR) or modified-release (MR)
tablets. Immediate release solid dosage forms permit the release of
most or all of the active ingredient over a short period of time,
such as 60 minutes or less, and make rapid absorption of the drug
possible. Modified release solid oral dosage forms permit the
sustained release of the active ingredient over an extended period
of time in an effort to maintain therapeutically effective plasma
levels over similarly extended time intervals and/or to modify
other pharmacokinetic properties of the active ingredient.
[0169] For the formulation of soft gelatin capsules, the active
substances may be admixed with e.g., a vegetable oil or
poly-ethylene glycol. Hard gelatin capsules may contain granules of
the active substances using either the above mentioned excipients
for tablets e.g., lactose, saccharose, sorbitol, mannitol, starches
(e.g., potato starch, corn starch or amylopectin), cellulose
derivatives or gelatine. Also liquids or semisolids of the drug can
be filled into hard gelatine capsules.
[0170] The compositions of the invention can also be introduced in
microspheres or microcapsules, e.g., fabricated from polyglycolic
acid/lactic acid (PGLA) (see, e.g., U.S. Pat. Nos. 5,814,344;
5,100,669 and 4,849,222; PCT Publications No. WO 95/11010 and WO
93/07861). Biocompatible polymers may be used in achieving
controlled release of a drug, include for example, polylactic acid,
polyglycolic acid, copolymers of polylactic and polyglycolic acid,
polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters,
polyacetals, polyhydropyrans, polycyanoacrylates, and cross-linked
or amphipathic block copolymers of hydrogels.
[0171] Memantine-coated non-pareil beads or seeds can also be used
according to the present invention (see Huang et al., Drug Dev Ind
Pharm. 2002; 28(5):593-9; and Ganesan et al., Boll Chim Farm.
2003;142(7):290-4).
[0172] Formulation of the 1-aminocyclohexane derivative in a
semi-solid or liquid form wherein the active ingredient, i.e. the
1-aminocyclohexane, is highly soluble in aqueous media may also be
used. The active ingredient may constitute between 0.1 and 99% by
weight of the formulation, more specifically between 0.5 and 20% by
weight for formulations intended for injection and between 0.2 and
50% by weight for formulations suitable for oral
administration.
[0173] In one embodiment of the invention, the 1-aminocyclohexane
derivative is administered in a modified release formulation.
Modified release dosage forms provide a means for improving patient
compliance and for ensuring effective and safe therapy by reducing
the incidence of adverse drug reactions. Compared to immediate
release dosage forms, modified release dosage forms can be used to
prolong pharmacologic action after administration, and to reduce
variability in the plasma concentration of a drug throughout the
dosage interval, thereby eliminating or reducing sharp peaks.
Modified release dosage forms are described in U.S. patent
application Ser. No. 11/155,330, incorporated by reference.
[0174] A modified release form dosage can comprise a core either
coated with or containing a drug. The core being is then coated
with a release modifying polymer within which the drug is
dispersed. The release modifying polymer disintegrates gradually,
releasing the drug over time. Thus, the outer-most layer of the
composition effectively slows down and thereby regulates the
diffusion of the drug across the coating layer when the composition
is exposed to an aqueous environment, i.e. the gastrointestinal
tract. The net rate of diffusion of the drug is mainly dependent on
the ability of the gastric fluid to penetrate the coating layer or
matrix and on the solubility of the drug itself.
[0175] In another embodiment of the invention, the
1-aminocyclohexane derivative is formulated in an oral, liquid
formulation. Liquid preparations for oral administration can take
the form of, for example, solutions, syrups, emulsions or
suspensions, or they can be presented as a dry product for
reconstitution with water or other suitable vehicle before use.
Preparations for oral administration can be suitably formulated to
give controlled or postponed release of the active compound. A
particular example of an oral time-controlled release
pharmaceutical formulation is described in U.S. Pat. No.
5,366,738.
[0176] For oral administration in liquid form, the
1-aminocyclohexane derivative can be combined with non-toxic,
pharmaceutically acceptable inert carriers (e.g., ethanol,
glycerol, water), suspending agents (e.g., sorbitol syrup,
cellulose derivatives or hydrogenated edible fats), emulsifying
agents (e.g., lecithin or acacia), non-aqueous vehicles (e.g.,
almond oil, oily esters, ethyl alcohol or fractionated vegetable
oils), preservatives (e.g., methyl or propyl-p-hydroxybenzoates or
sorbic acid), and the like. Stabilizing agents such as antioxidants
(BHA, BHT, propyl gallate, sodium ascorbate, citric acid) can also
be added to stabilize the dosage forms. For example, solutions may
contain from about 0.2% to about 20% by weight of memantine, with
the balance being sugar and mixture of ethanol, water, glycerol and
propylene glycol. Optionally such liquid formulations may contain
coloring agents, flavoring agents, saccharine and
carboxymethyl-cellulose as a thickening agent or other
excipients.
[0177] In another embodiment, a therapeutically effective amount of
the 1-aminocyclohexane derivative is administered in an oral
solution containing a preservative, a sweetener, a solubilizer, and
a solvent. The oral solution may include one or more buffers,
flavorings, or additional excipients. In a further embodiment, a
peppermint or other flavoring is added to the 1-aminocyclohexane
derivative oral liquid formulation.
[0178] For administration by inhalation, the 1-aminocyclohexane
derivative can be conveniently delivered in the form of an aerosol
spray presentation from pressurized packs or a nebulizer, with the
use of a suitable propellant, e.g., dichlorodifluoromethane,
trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide,
or other suitable gas. In the case of a pressurized aerosol, the
dosage unit can be determined by providing a valve to deliver a
metered amount. Capsules and cartridges of, e.g., gelatin for use
in an inhaler or insufflator can be formulated containing a powder
mix of the compound and a suitable powder base such as lactose or
starch.
[0179] Solutions for parenteral applications by injection can be
prepared in an aqueous solution of a water-soluble pharmaceutically
acceptable salt of the active substances, preferably in a
concentration of from about 0.5% to about 10% by weight. These
solutions may also contain stabilizing agents and/or buffering
agents and may conveniently be provided in various dosage unit
ampoules.
[0180] Dosage units for rectal application can be solutions or
suspensions or can be prepared in the form of suppositories or
retention enemas comprising the 1-aminocyclohexane derivative in a
mixture with a neutral fatty base, or gelatin rectal capsules
comprising the active substances in admixture with vegetable oil or
paraffin oil.
[0181] The formulations of the invention can be delivered
parenterally, i.e., by intravenous (i.v.), intracerebroventricular
(i.c.v.), subcutaneous (s.c.), intraperitoneal (i.p.),
intramuscular (i.m.), subdermal (s.d.), or intradermal (i.d.)
administration, by direct injection, via, for example, bolus
injection or continuous infusion. Formulations for injection can be
presented in unit dosage form, e.g., in ampoules or in multi-dose
containers, with an added preservative. Alternatively, the active
ingredient can be in powder form for reconstitution with a suitable
vehicle, e.g., sterile pyrogen-free water, before use. For parental
administration, the rate of infusion must be carefully controlled
due to the relatively long half-life of me the 1-aminocyclohexane
derivative mantine in the blood stream.
[0182] The invention also provides a pharmaceutical pack or kit
comprising one or more containers containing the 1-aminocyclohexane
derivative and, optionally, more of the ingredients of the
formulation. In a specific embodiment, memantine is provided as an
oral solution (2 mg/ml) for administration with the use of a 2
teaspoon capacity syringe (dosage KORC.RTM.). Each oral syringe has
blue hatch marks for measurement, with lines on the right side of
the syringe (tip down) representing tsp units, and those on the
left representing ml units.
[0183] The optimal therapeutically effective amount should be
determined experimentally, taking into consideration the exact mode
of administration, from in which the drug is administered, the
indication toward which the administration is directed, the subject
involved (e.g., body weight, health, age, sex, etc.), and the
preference and experience of the physician or veterinarian in
charge.
[0184] Toxicity and therapeutic efficacy of the compositions of the
invention can be determined by standard pharmaceutical procedures
in experimental animals, e.g., by determining the LD50 (the dose
lethal to 50% of the population) and the ED50 (the dose
therapeutically effective in 50% of the population). The dose ratio
between therapeutic and toxic effects is the therapeutic index and
it can be expressed as the ratio ED50/LD50. Compositions that
exhibit large therapeutic indices are preferred.
[0185] Suitable daily doses of the active compounds of the
invention in therapeutic treatment of humans are about 0.01-10
mg/kg bodyweight on peroral administration and 0.001-10 mg/kg
bodyweight on parenteral administration. For adults, suitable daily
doses of memantine or neramexane are within the range from about
1.25 mg to about 100 mg per day, preferably, from about 20 to about
40 mg per day. For pediatric subjects aged 4-14, it is preferred
that memantine is administered as an oral, liquid dosage form, at
about 0.5 mg/day, up to a maximum dose of 10 mg/day. Titration to
the maximum dose over about 4 weeks from a lower initial starting
dose, e.g., about 1.25 mg/day, with weekly increases by about 1.25
mg/day, is highly recommended. For liquid, oral administration,
memantine is dissolved in about one-half the liquid equivalent of
the dose. For example, 12.5 mg memantine will be dissolved in 10 ml
of the liquid formulation for administration.
[0186] Treatment duration can be short-term, e.g., several weeks
(for example 8-14 weeks), or long-term until the attending
physician deems further administration no longer is necessary.
[0187] The 1-aminocyclohexane derivative may be administered as a
monotherapy, or in combination with another agent prescribed for
the treatment of MS, EL or PBA.
[0188] The 1-aminocyclohexane derivative may be administered in
combination with an immunomodulator, including glatiramer
acetate.
[0189] The term "combination" applied to active ingredients is used
herein to define a single pharmaceutical composition (formulation)
comprising two active agents (e.g., a pharmaceutical composition
comprising a 1-aminocyclohexane derivative and an immunomodulator)
or two separate pharmaceutical compositions, each comprising an
active agent (e.g. a pharmaceutical composition comprising a
1-aminocyclohexane derivative or an immunomodulator), to be
administered conjointly.
[0190] Within the meaning of the present invention, the term
"conjoint administration" is used to refer to administration of the
1-aminocyclohexane and a second active agent (e.g. an
immunomodulator) simultaneously in one composition, or
simultaneously in different compositions, or sequentially. For the
sequential administration to be considered "conjoint", however, the
1-aminocyclohexane derivative and the second active agent must be
administered separated by a time interval which still permits the
resultant beneficial effect for treating MS, EL or PBA in a
mammal.
EXAMPLES
[0191] The following example illustrates the invention without
limiting its scope.
Example 1
Double Blind Placebo Controlled Pilot Trial of Memantine for
Cognitive Impairment in Multiple Sclerosis
[0192] The objective of this pilot project is to conduct a clinical
trial to assess the efficacy of memantine as a treatment for
cognitive dysfunction in multiple sclerosis (MS). We hypothesize
that MS patients with cognitive impairment treated with memantine
will demonstrate an improvement in performance on a
neuropsychological test battery as compared to placebo treated
patients.
[0193] Cognitive dysfunction is a major cause of disability in
multiple sclerosis. The estimated prevalence of cognitive
dysfunction in the MS population is 45% to 65%. MS patients with
cognitive dysfunction have fewer social interactions, more sexual
dysfunction, greater difficulty with household tasks and higher
unemployment than those with normal cognition. At present, there is
no effective pharmacological symptomatic treatment for the
cognitive dysfunction of MS. One agent that may have some benefit
in treating this condition is the N-methyl-D-aspartate (NMDA)
receptor antagonist memantine.
[0194] Memantine is a NMDA antagonist that has been shown to be
effective in treating Alzheimer's disease. Glutamate toxicity has
been implicated in the pathogenesis of a variety of neurologic
diseases, including MS. Glutamate receptor activation may be
involved both in mediation of neural injury and in neuronal
dysfunction. By blocking NMDA receptors, memantine may both improve
neuronal function, explaining symptomatic improvement in some
Alzheimer's patients, and slow progressive neuronal death,
potentially resulting in a slowing of cognitive decline in
Alzheimer's patients. The pathogenesis of cognitive dysfunction in
MS relates as least in part to the extent of cerebral
demyelination, axonal loss and atrophy. Some cognitive dysfunction
is reversible. Reduction in inflammation can result in improvement
in cognitive performance. This investigation will show the role of
NMDA receptors and glutamate toxicity may play in the treatment of
cognitive dysfunction in MS.
Study Design
[0195] A placebo-controlled, double-blinded, randomized,
parallel-group pilot study of 21 weeks duration is planned for MS
patients with cognitive impairment. There will be 20 patients per
treatment arm. The intervention arm will receive 20 mg of memantine
a day. Randomization into each treatment arm will be stratified on
age. A double-blind, placebo controlled trial is critical to
perform even for a pilot trial. Both learning and placebo effect
are likely to improve the cognitive performance of some subjects.
An open labeled trial would likely show some improvement in the
patients but the results would not be interpretable.
Statistical Procedures and Populations for Analysis
[0196] The Scheduled Visits will be as follows:
[0197] Visit 1: The subject will receive consent form. After
signing, the visual acuity will be tested. They will receive the
first half of the neuropsychological test battery, which includes
the Paced Auditory Serial Addition Test (PASAT) and California
Verbal Learning Test II (CVLT-II). They will also receive the Beck
Depression Inventory (BDI). Women of childbearing potential will be
asked to give a urine sample for a pregnancy test (beta HCG). At
this point, patients will be informed whether they have met the
full criteria for enrollment. If they qualify then they will
receive the second half of the neuropsychological tests (Controlled
Oral Word Association Test, Stroop Color And Word Association Test,
Symbol Digit Modalities Test and Useful Field Of Vision Test).
[0198] This visit will last approximately 11/2 hours if the patient
does not qualify for the study and 2 hours if they qualify.
[0199] Visit 2: The subjects will receive the Fatigue Severity
Scale (FSS) and Modified Fatigue Impact Scale (MFIS), physical exam
and a neurological exam. This visit will last 1 hour.
[0200] Visit 3: The complete neuropsychological test battery will
be performed. The Medical Outcomes Study 36 Item Short Form Health
Survey (SF-36) and the Perceived Deficits Questionnaire (PDQ) from
the Multiple Sclerosis Quality of Life Inventory (MSQLI) will be
administered. This visit will last 2 hours.
[0201] Visit 4: The complete neuropsychological test battery will
be administered again. Memantine and placebo pills will be
dispensed. The starting dose of memantine will be 5 mg once daily.
The dose will be increased in 5 mg increments to 10 mg/day (5 mg
twice a day), 15 mg/day (5 mg and 10 mg as separate doses), and 20
mg/day (10 mg twice a day) over 4 weeks and then continued at 20 mg
for the rest of the study. This visit will last about 11/2
hours.
[0202] Telephone follow-up visits will be carried-out for all
enrolled subjects four and eight weeks after visit #4. These calls
will review study procedures, check for compliance and reports of
side effects. The total time for the telephone visit will be 15
minutes.
[0203] Visit 5: Subjects will return to clinic for the final
assessment 4 weeks after the second telephone follow-up visit. At
this visit, subjects will complete the full neuropsychological test
battery. The SF-36 and PDQ, BDI, FSS, and MFIS will be
administered. A repeat neurological and physical exam will be
performed. This visit will last 21/2 hours.
[0204] Primary Outcome: Neuropsychological Test Battery: Each test
will include the neuropsychological test battery which is a
commonly used cognitive measure of established validity and
reliability. This battery will be tailored to assess those
cognitive domains that are most frequently affected in MS. The
tests to be included in the battery are the:
[0205] 1. Paced Auditory Serial Addition Test: A measure of
auditory information processing speed.
[0206] 2. California Verbal Learning Test II: A measure of verbal
learning/memory.
[0207] 3. Controlled Oral Word Association Test: A measure of
phonemic fluency.
[0208] 4. Stroop Color and Word Test: A measure of concentration
and attention.
[0209] 5. Symbol Digit Modalities Test: A measure of information
processing speed and visual tracking.
[0210] 6. Useful Field of Vision Test: A test of visual information
processing and divided attention.
[0211] Secondary Outcomes:
[0212] 1. Fatigue Severity Scale: a fatigue severity scale that has
used in MS clinical trials.
[0213] 2. Modified Fatigue Impact Scale: alternate fatigue scale
with MS specific items.
[0214] 3. MS Quality of Life Inventory: An MS-specific
health-related quality of life instrument. Only the health survey
questionnaire (SF-36) and the Perceived Deficit Questionnaire will
be used from the MSQLI.
[0215] 4. Beck Depression Inventory: a frequently used measure of
depression.
[0216] Inclusion Criteria:
[0217] 1. A diagnosis of multiple sclerosis as defined by the
McDonald criteria. Patients with relapsing-remitting, secondary
progressive, and primary progressive forms of MS will be
eligible.
[0218] 2. Age between 18 and 60 years.
[0219] 3. Demonstrated cognitive dysfunction at screening defined
as a score in the range of 0.5 to 2.5 standard deviations below the
mean on the PASAT or the CVLT-II.
[0220] Exclusion Criteria:
[0221] 1. A history of major depression, psychosis, or a score
>19 on the Beck's Depression Inventory.
[0222] 2. Corrected binocular visual acuity worse than 20/50; any
impairment of binocular color vision.
[0223] 3. Patients that do not speak English as a primary language
(fluency may impact performance).
[0224] 4. A clinically significant MS exacerbation within 30 days
of the screening
[0225] 5. Pregnancy
[0226] 6. Renal insufficiency.
[0227] 7. History of seizures.
[0228] 8. Patients using acetazolamide (Diamox, Ak-sol,
Storzolamide), dichlorphenamide (Daranide), methazolamide
(Neptazane) or topiramate (Topamax), dextrometorphan (Robitussin DM
and other cold remedies), amantadine (Symmetrel).
Data Analysis
[0229] The two groups (memantine and placebo) will be compared for
randomization inequity for demographic and disease severity
factors. Because of possible effects of learning, the third battery
will be considered as baseline. The primary analysis will use a
repeated measure ANOVA comparing the response in the two groups. A
two-sided alpha value of 0.05 is defined as statistical
significance. All primary outcome and secondary variables will be
analyzed.
Discussion
[0230] It is anticipated that the memantine treated group will show
an improvement in performance on the cognitive test battery as
compared to the placebo group.
Example 2
Use of Neramexane in the EAE Model in Mice
[0231] Induction of EAE. Induction of EAE in animal models is well
known in the art. (Raine, Chapter 16, Handbook of Clinical
Neurology, vol. 3(47): Demyelinating Diseases, Koetsier, ed.,
(Elsevier Science Publishers 1985). In the present protocol, 6-8
week ABH mice are immunized with mouse spinal cord homogenate in
Freund's complete adjuvant on day 0 & 7. (Baker et al. 1990. J.
Neuroimmunol 28:261 O'Neill et al 1992. J. Neuroimmunol. 38:53).
Animals will develop relapsing remitting episodes of paralysis at
approximately 3-4 week intervals. These will be monitored daily
from day 11 onwards to ensure severity levels of paralysis and
maintained with humane limits according to the Home Office, Animals
(Scientific Procedures) Act (1981). Spasticity (stiff hind limbs)
after 2-3 relapse episodes (approximately 80-120 days
post-induction) will be allowed to develop. Animals with visually
spastic limbs will be selected for assessment of the TEST
compound.
[0232] Resistance to flexion against a strain gauge will be the
primary assessment (Baker et al. 2000. Nature), secondary outcome
measures will be the presence or absence of spastic tails. See
FIGS. 1A and 1B.
[0233] Spasticity. The "stiffness" of spastic limbs is measured
using a purpose built strain gauge, and assessed by the resistance
force against hindlimb flexion. The limb is extended manually twice
prior to measurement of each limb. Limbs showing severe crossing or
flexion will not be analyzed. The signal is amplified and digitized
using DAS16 card (Amplicon, Brighton UK.) and acquired using
Dacquire V10 software and analyzed using Spike 2 software (Baker et
al 2000). Left and right hindlimbs are analyzed alternately and
typically 5-8 readings per limb were measured at each time point.
The mean values will be calculated and converted to forces in
Newtons. Data will be analyzed using one-way repeated measures
analysis of variance (ANOVA) incorporating Student-Newman-Keuls
posthoc test. Differences to baseline will also be compared using
Paired t tests.
[0234] Administration of Compound. The TEST compounds are dissolved
in vehicle (to be supplied by the SPONSOR-preferably this will be a
saline solution) using doses (to be supplied by the SPONSOR). These
will be delivered by the intravenous, intraperitoneal or oral route
(to be supplied by the sponsor). Resistance to flexion will be
assessed at 10 minutes 30 minutes and 60 minutes following
intravenous, intraperitoneal injection, 30, 60 and 90 minutes after
oral administration. (Escalating doses (up to three) may be used in
the same cohort of animals following wash-out to allow for direct
comparison of the dose response).
[0235] This may be repeated in drug naive animals and the longevity
of the effect assessed at hourly intervals up to X hours plus at 24
hours after administration.
Results--3.1 mg/kg. See FIG. 2.
[0236] One Way Repeated Measures Analysis of Variance
TABLE-US-00001 Normality Test: Passed (P = 0.043) Equal Variance
Test: Passed (P = 0.448) Treatment Name N Missing Mean Std Dev SEM
0 minN 13 0 0.593 0.186 0.0517 10 minN 13 0 0.422 0.171 0.0475 30
minN 13 0 0.451 0.141 0.0392 60 minN 13 0 0.374 0.143 0.0398 Source
of Variation DF SS MS F P Between Subjects 12 0.906 0.0755 Between
Treatments 3 0.345 0.115 11.844 <0.001 Residual 36 0.349 0.00970
Total 51 1.599
[0237] The differences in the mean values among the treatment
groups are greater than would be expected by chance; there is a
statistically significant difference (P=<0.001). To isolate the
group or groups that differ from the others use a multiple
comparison procedure.
[0238] Power of performed test with alpha=0.050:0.999
[0239] All Pairwise Multiple Comparison Procedures
(Student-Newman-Keuls Method):
TABLE-US-00002 Comparisons for factor: Diff of Comparison Means p q
P P < 0.050 ominN vs. 60 minN 0.218 4 7.997 <0.001 Yes ominN
vs. 10 minN 0.171 3 6.262 <0.001 Yes ominN vs. 30 minN 0.142 2
5.188 <0.001 Yes 30 minN vs. 60 minN 0.0767 3 2.808 0.130 No 30
minN vs. 10 minN 0.0293 2 1.074 0.453 Do Not Test 10 minN vs. 60
minN 0.0474 2 1.734 0.228 Do Not Test
[0240] A result of "Do Not Test" occurs for a comparison when no
significant difference is found between two means that enclose that
comparison. For example, if you had four means sorted in order, and
found no difference between means 4 vs. 2, then you would not test
4 vs. 3 and 3 vs. 2, but still test 4 vs. 1 and 3 vs. 1 (4 vs. 3
and 3 vs. 2 are enclosed by 4 vs. 2: 4 3 2 1). Note that not
testing the enclosed means is a procedural rule, and a result of Do
Not Test should be treated as if there is no significant difference
between the means, even though one may appear to exist.
Results--6.2 mg/kg. See FIG. 3.
One Way Repeated Measures Analysis of Variance
TABLE-US-00003 [0241] Normality Test: Passed (P > 0.200) Equal
Variance Test: Passed (P = 0.115) Treatment Name N Missing Mean Std
Dev SEM 0 min 11 0 0.567 0.278 0.0837 10 min 11 0 0.567 0.253
0.0763 30 min 11 0 0.450 0.201 0.0607 60 min 11 0 0.395 0.127
0.0384 Source of Variation DF SS MS F P Between Subjects 10 1.735
0.173 Between Treatments 3 0.246 0.0819 10.146 <0.001 Residual
30 0.242 0.00807 Total 43. 2.223
[0242] The differences in the mean values among the treatment
groups are greater than would be expected by chance; there is a
statistically significant difference (P=<0.001). To isolate the
group or groups that differ from the others use a multiple
comparison procedure.
[0243] Power of performed test with alpha=0.050: 0.994.
[0244] All Pairwise Multiple Comparison Procedures
(Student-Newman-Keuls Method):
TABLE-US-00004 Comparisons for factor: Comparison Diff of Means p q
P P < 0.050 0 min vs. 60 min 0.172 4 6.342 <0.001 Yes 0 min
vs. 30 min 0.117 3 4.316 0.013 Yes 0 min vs. 10 min 0.0000691 2
0.00255 0.999 No 10 min vs. 60 min 0.172 3 6.340 <0.001 Yes 10
min vs. 30 min 0.117 2 4.314 0.005 Yes 30 min vs. 60 min 0.0549 2
2.026 0.162 No Results --12.3 mg/kg. See FIG. 4.
One Way Repeated Measures Analysis of Variance
TABLE-US-00005 [0245] Normality Test: Passed (P = 0.013) Equal
Variance Test: Passed (P = 0.928) Treatment Name N Missing Mean Std
Dev SEM 0 min 14 0 0.453 0.214 0.0572 10 min 14 0 0.339 0.165
0.0441 30 min 14 0 0.350 0.154 0.0412 60 min 14 0 0.263 0.0892
0.0238 Source of Variation DF SS MS F P Between Subjects 13 1.168
0.0898 Between Treatments 3 0.255 0.0849 17.160 <0.001 Residual
39 0.193 0.00495 Total 55 1.615
[0246] The differences in the mean values among the treatment
groups are greater than would be expected by chance; there is a
statistically significant difference (P=<0.001). To isolate the
group or groups that differ from the others use a multiple
comparison procedure.
[0247] Power of performed test with alpha=0.050: 1.000
[0248] All Pairwise -Multiple Comparison Procedures
(Student-Newman-Keuls Method)
TABLE-US-00006 Comparisons for factor: Comparison Diff of Means p q
P P < 0.050 0 min vs. 60 min 0.189 4 10.079 <0.001 Yes 0 min
vs. 10 min 0.114 3 6.050 <0.001 Yes 0 min vs. 30 min 0.103 2
5.487 <0.001 Yes 30 min vs. 60 min 0.0863 3 4.592 0.007 Yes 30
min vs. 10 min 0.0106 2 0.564 0.693 No 10 min vs. 60 min 0.0757 2
4.028 0.007 Yes
[0249] All 3 doses of Neramexane used in the study reduced the
level of hind limb spasticity present in the affected mice.
[0250] The present invention is not to be limited in scope by the
specific embodiments described herein. Indeed, various
modifications of the invention in addition to those described
herein will become apparent to those skilled in the art from the
foregoing description. Such modifications are intended to fall
within the scope of the appended claims.
[0251] All patents, applications, publications, test methods,
literature, and other materials cited herein are hereby
incorporated by reference.
* * * * *